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Journal of Virology, June 2008, p. 5912-5921, Vol. 82, No. 12
0022-538X/08/$08.00+0     doi:10.1128/JVI.00389-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Characterization of Neutralizing Antibody Responses Elicited by Clade A Envelope Immunogens Derived from Early Transmitted Viruses

Zane Kraft,¹ Katharine Strouss,¹ William F. Sutton,^1, Brad Cleveland,² For Yue Tso,^2, Patricia Polacino,³ Julie Overbaugh,⁴ Shiu-Lok Hu,^2,3 and Leonidas Stamatatos^1,5*

Seattle Biomedical Research Institute, Seattle, Washington 98109,¹ Department of Pharmaceutics,² Washington National Primate Research Center, Seattle, Washington 98195,³ Division of Human Biology, Fred Hutchinson Cancer Research Institute, Seattle, Washington 98109,⁴ Department of Pathobiology, University of Washington, Seattle, Washington 98109⁵

Received 22 February 2008/ Accepted 1 April 2008

The vast majority of studies with candidate immunogens based on the human immunodeficiency virus envelope (Env) have been conducted with Env proteins derived from clade B viruses isolated during chronic infection. Whether non-clade B Env protein immunogens will elicit antibodies with epitope specificities that are similar to those of antibodies elicited by clade B Envs and whether the antibodies elicited by Envs derived from early transmitted viruses will be similar to those elicited by Envs derived from viruses isolated during chronic infection are currently unknown. Here we performed immunizations with four clade A Envs, cloned directly from the peripheral blood of infected individuals during acute infection, which differed in lengths and extents of glycosylation. The antibody responses elicited by these four Envs were compared to each other and to those elicited by a well-characterized clade B Env immunogen derived from the SF162 virus, which was isolated during chronic infection. Only one clade A Env, the one with the fewer glycosylation sites, elicited homologous neutralizing antibodies (NAbs); these did not target the V1, V2, or V3 regions. In contrast, all four clade A Envs elicited anti-V3 NAbs against "easy-to-neutralize" clade B and clade A isolates, irrespective of the variable region length and extent of glycosylation of the Env used as an immunogen. These anti-V3 NAbs did not access their epitopes on homologous and heterologous clade A, or B, neutralization-resistant viruses. The length and extent of glycosylation of the variable regions on the clade A Env immunogens tested did not affect the breadth of the elicited NAbs. Our data also indicate that the development of cross-reactive NAbs against clade A viruses faces similar hurdles to the development of cross-reactive anti-clade B NAbs.

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* Corresponding author. Mailing address: Seattle Biomedical Research Institute, 307 Westlake Avenue North, Seattle, WA 98109. Phone: (206) 256-7200. Fax: (206) 256-7229. E-mail: leo.stamatatos{at}sbri.org

Published ahead of print on 9 April 2008.

Present address: Oregon Health & Science University, Beaverton, OR 97006.

Present address: University of Nebraska, Lincoln, NE 68588.

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Journal of Virology, June 2008, p. 5912-5921, Vol. 82, No. 12
0022-538X/08/$08.00+0     doi:10.1128/JVI.00389-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.